Can We Get There From Here?
The Huntington’s Disease Community’s Strategic Plan for the Cure
Part One
Last week, in a speech to the Society for Neuroscience, former Intel co-founder and CEO Andrew Grove called for a revolution in biomedical research. The week before, Michael J. Fox, the likeable and well known TV and movie actor, wrote a column for Forbes called “Who’s in Charge of Cures?’ in which he called for creative solutions to bridge the gap between basic researchers and pharmaceutical companies.
Both of these men have Parkinson’s Disease and both are frustrated. Both have seen industry-transforming technological changes in their own fields and want to see that same American ingenuity being applied to cure neurodegenerative disorders.
Grove and Fox agree that there is a huge gap between academic research into diseases and the pharmaceutical industry. Fox wrote, “A researcher in a university lab needs to focus on the kinds of incremental steps forward that get published in scientific journals, while a decision-maker in an industry setting is on the hunt for a massively profitable blockbuster drug. The philosophical and funding gap between these two short-term goals is a chasm, and so far, it's shown no signs of bridging itself.”
The question that HD families need answered is, “What is the Huntington’s Disease community doing to bridge the gap and bring about real treatments?” Do we have a plan to translate research findings from the lab into treatments in the clinic?
We know that Huntington’s Disease research has attracted some of the best and brightest academic scientists there are. We know from our annual HDSA conventions as well as reports from research conferences that they are focused on understanding the disease so that it can be treated and that they share their results with each other and with HD families.
We know that there is an exciting amount of research going on into Huntington’s Disease. Nearly every week, there is another press release announcing a new research finding, and often the university or research facility’s PR person makes sure to put in the headline or text the idea that the new information may lead to a cure. It’s encouraging to read these reports but hard to put them in context with all that is going on.
After awhile HD family members start to wonder what progress is really being made. “Wait a minute, wasn’t a different line of research last month supposed to lead to the cure?” And we might wonder why we are still funding basic research when compounds are already going into clinical trials and what the excitement over drug discovery and development is all about.
What we HD families may not be aware of is that the Huntington’s Disease community does indeed have a strategic research plan and that Huntington’s Disease research is happening in parallel – basic research, target validation, drug discovery and development, preclinical research, and clinical trials. Different approaches are being pursued simultaneously and there are dozens of drugs in the pipeline. There will be no “Oh no, back to the drawing board!” disappointments in HD research. When an approach or a drug is no longer promising, resources are quickly redirected towards those that are.
The Huntington’s Disease Strategic Plan
A good way to learn about the HD strategic research plan is to attend the annual HDSA convention or to read convention reports. In 2005, Dr. Robert Pacifici, newly hired Chief Scientific Officer for CHDI (Cure Huntington’s Disease Initiative), electrified the audience with the strategic plan to develop treatments. His presentation showed family members how the different stages research fit together and he outlined the steps needed to translate research findings from the lab to treatments in the clinic.
In subsequent conventions, Dr. Pacifici and Dr. James Gusella have updated the HD community on progress in achieving goals and objectives.
Dr. Gusella, Professor of Neurogenetics at Harvard Medical School, is the HDSA Medical/Scientific Advisory Committee Chair and a Coalition member.
Basic Research
Basic research into the nature of the disease process is being conducted around the world and is supported by governments, foundations, and grants from HD societies, including the HDSA. Dr. Pacifici and Dr. Gusella answer questions from the audience at the 2007 HDSA convention.
In an interview in Newsweek just before his address to the Society for Neuroscience, Andrew Grove stated his belief that there is too much conformity in academic research into diseases and argued that there needs to be more room for ‘wild ducks.’
New ideas are important and part of the strategic plan is to promote them by encouraging talented scientists to go into Huntington’s Disease research and by funding innovative ideas. As Dr. Pacifici puts it, the ‘ah ha’ moment can come out of left field. CHDI maintains biological and chemical repositories to make it easier for academic researchers to participate in HD research. HDSA awards research grants that serve as vital seed funding for new or innovative research and awards fellowships to promising postdoctoral scientists in the early stages of their career.
In the last decade, much has been discovered about what goes wrong in Huntington’s Disease. Some of the major research findings about how the HD protein causes dysfunction and cell death have been discovered by members of HDSA’s Coalition for the Cure. The Coalition is made up of 16 international labs.
At the 2007 convention in Oklahoma, Dr. Gusella explained the goals of the Coaltion for the Cure. They are to 1) Discover the biochemical differences that occur in HD," and to “2) Define which ones are critical in the disease process.” These will be the targets for CHDI’s translational research.
The Coalition has been focusing on answering key questions about the pathologies which appear to be most critical in Huntington’s disease. These are:
- mitochondrial dysfunction and energy metabolism
- folding, aggregation and clearance of the HD protein
- huntingtin proteolysis and post-translational modification
- gene transcription
- function of the huntingtin's protein.
This focus has been paying off in insights about the disease process. In a study published this summer, Coalition member Dr. Marcy MacDonald and colleagues showed that the mitochondria, the energy factories of the cell, are not defective in HD, but rather are not being managed properly.
As more has been learned about the disease process, more research funding is being devoted to target validation. A target for drugs or gene therapy would be an enzyme, protein, receptor, or gene that contributes to the disease process.
In the last year or so, there have been several exciting studies published which have identified drugs for drug development. In the summer of 2006, Coalition member Dr. Michael Hayden and his colleagues identified caspase six as a potential target. Caspace six is an enzyme which is implicated in the cutting up of the HD protein into toxic fragments. HD mice which were also engineered to be resistant to caspase six never developed the disease. CHDI has been funding research into the development of a safe and effective inhibitor of caspase six.
This summer Dr. Ray Truant and Ph.D. candidate Randy Atwal Singh found that the huntingtin’s protein moves into the nucleus of the cell in response to stress but the mutant (HD) version has trouble exiting and accumulates, causing damage. They are now working on developing an inhibitor of the molecular ‘zip code’ (a kinase, which is a certain type of enzyme) which directs the huntingtin’s protein into the nucleus.
Also this summer, coalition member Dr. Elena Cattaneo and her colleagues have shown how the huntingtin’s protein interferes with gene transcription. In HD, a repressor protein known as REST enters the cell’s nucleus and suppresses key genes such as the one for brain derived neurotrophic factor which protects striatal neurons and encourages neurogenesis. A cell based assay has found a compound which upregulates the suppressed genes and increased the viability of the cell.
There is still more to be learned about the Huntington’s disease process and basic research still has a major role to play, but the knowledge already gained is likely to lead to significant treatments.
Basic research is followed by drug discovery and development where we have even more exciting news to discuss. I’ll talk more about what’s happening in drug discovery and development in the next article.
- Marsha L. Miller, Ph.D., November 13, 2007